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International Team Tracks Down Tuberculosis Susceptibility Locus in Africa

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – An international research team led by investigators in the UK and Germany reported in the early, online version of Nature Genetics yesterday that they have identified a genetic locus linked to tuberculosis susceptibility through genome-wide association studies in two African countries.

The group combined data on more than 11,000 individuals from two GWAS studies done in Ghana and The Gambia. Results from these studies, as well as replication testing involving individuals from Ghana and Malawi, identified a chromosome 18 locus distinct from TB susceptibility variants in the major histocompatibility, or MHC locus, which contributes to immune system function.

"Although we know of other genetic variants which increase susceptibility to TB, this is the first to have been identified using a genome-wide association study," co-corresponding author Adrian Hill, a human genetics researcher at the Wellcome Trust Centre for Human Genetics, said in a statement.

"This is very important as it demonstrates that we can do these studies — which have been so successful in European populations — in African populations, which suffer the greatest burden from infectious diseases," he added.

Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis bacteria, affects millions of people around the world and is especially common in parts of sub-Saharan Africa.

While TB susceptibility seems to rely, in part, on genetic factors, the researchers explained, most genetic changes implicated in TB risk so far have fallen in genes in the MHC locus, which tends to influence susceptibility to a range of infectious diseases.

"In general, finding convincing non-MHC susceptibility loci across populations for infectious diseases has been difficult, even in individuals of European ancestry," they noted.

Finding genetic variants that increase or decrease susceptibility to infection can be even trickier in African populations, they explained, which are known to have high genetic diversity and low linkage disequilibrium.

"Our challenges here were two-fold," co-lead author Fredrik Vannberg, a post-doctoral researcher in Hill's Wellcome Trust Centre for Human Genetics lab, said in a statement. "We were looking for human genetic variants affecting susceptibility to a pathogen which itself differs genetically from region-to-region, and we were searching for these variants in African populations, which are genetically very diverse."

Nevertheless, there is mounting optimism about the prospect of doing disease association studies in Africa. Last year, for instance, researchers involved in the MalariaGEN project published a proof-of-principle study describing how they combined GWAS and targeted re-sequencing to find variants associated with severe malaria in The Gambia.

For the current study, the team relied on large sample sizes and extensive replication studies to tackle the genetic diversity in the African populations tested.

For the discovery phase of the effort, the researchers integrated data from a new GWAS — involving 921 individuals with tuberculosis and 1,740 unaffected controls in Ghana — with genotype data generated by the Wellcome Trust Case Control Consortium for 1,316 tuberculosis cases and 1,382 controls in The Gambia.

Individuals in Ghana were genotyped at more than 740,000 autosomal SNPs using the Affymetrix SNP 6.0 array, while genotype data at more than 350,000 autosomal SNPs had been generated with the Affymetrix GeneChip 500K for individuals in The Gambia.

Based on combined data at nearly 334,000 SNPs in the two West African countries as well as analyses of HapMap data on Yoruban and non-African populations, the researchers found 17 candidate SNPs.

They tested these SNPs in another 1,076 Ghanaians with tuberculosis and 1,611 Ghanaian controls to narrow their search to a pair of SNPs, which were subsequently assessed in another 150 cases and 2,214 controls from Ghana, a few hundred Ghanaian family trios, as well as 236 cases and 779 controls from Malawi.

One SNP — called rs4331426 — was most strongly associated with tuberculosis following these replication studies. The variant, which falls in a gene-poor region on chromosome 18, is fairly common within Africa but far more rare in populations from other parts of the world, researchers noted.

Meanwhile, a chromosome 2 variant tied to TB in the first two groups did not associate with disease susceptibility in the second replication study. When the team looked specifically at genes implicated in past TB studies, they found weak to moderate associations with some of these genes as well.

More research is needed to understand the functional effects of the newly identified variants and their role in TB. Even so, the team also expressed optimism about the findings — as well as the feasibility of doing large GWAS in African populations in general.

"This work demonstrated that a new non-MHC locus can be identified in a major infectious disease caused by a highly polymorphic pathogen and suggests that many further loci may be identifiable with GWAS of sufficient sample size, even in African populations, which suffer the greatest burden of communicable diseases," they concluded.

Researchers from the Wellcome Trust and National Institutes of Health plan to continue exploring the genetic and environmental underpinnings of infectious and hereditary disease in Africa through the Human Heredity and Health in Africa, or H3Africa, project.

"The approach and findings from this study for TB, and previous research from the MalariaGEN project, provide proof-of-principle that genome-wide approaches can yield fruitful results in African populations and sets a good precedent for the H3 Africa initiative," National Human Genome Research Institute Center for Research on Genomics and Global Health Director Charles Rotimi, who is heading the NIH arm of H3Africa, said in a statement.